Myofascial trigger points are not an isolated neuromusculoskeletal phenomenon and have been implicated in systemic, visceral, and metabolic pathology, as a side effect of some medications and in the presence of psychological risk factors. This complexity can complicate adequate screening of patients prior to choosing dry needling as a treatment intervention. Regardless of whether clinicians practice in a direct access setting, they should be cognizant of medical conditions, comorbidities, and risk factors that will influence clinical decisions for dry-needling appropriateness, technique chosen, and potential adverse responses to treatment. Of primary concern are conditions that can either manifest with myalgia and/or myopathy or masquerade as a more common musculoskeletal condition. This clinical commentary reviews system-specific considerations and other common disorders that should be screened for and discusses not only whether dry needling is appropriate but comments on technique and dosage considerations when initiating dry needling.